The Effect of Cardiac Resynchronization Therapy on Right Ventricular Function: A Systematic Review and Meta-Analysis

Background: Right ventricular (RV) failure is an important predicting factor regarding overall and event-free survival regardless of baseline left ventricular (LV) function in patients with severe heart failure (HF). Previous studies have indicated that cardiac resynchronization therapy (CRT) improves LV and RV reverse remodeling in patients with systolic dyssynchrony within the left ventricle. However, there is conflicting evidence regarding the role of CRT in RV function. The aim of this systematic review and meta-analysis was to examine the implications of CRT on RV function indices. Methods: A systematic literature search was conducted using the MedLine and EMBASE databases and the Cochrane Library from their inception until 18 March 2024. Eligible were studies providing information on RV function indices, both at baseline and after CRT. Evidence was summarized using random-effects meta-analytic models. Results: In total, 30 studies were deemed eligible. CRT resulted in a significant improvement in right ventricular fractional area change (mean difference (MD) 5.11%, 95% confidence interval (CI) 2.83 to 7.39), tricuspid annular plane systolic excursion (TAPSE, MD 1.63 mm, 95% CI 1.10 to 2.16), and myocardial systolic excursion velocity (MD 1.85 cm/s, 95% CI 1.24 to 2.47) as well as a significant decrease in pulmonary artery systolic pressure (MD −6.24 mmHg, 95% CI −8.32 to −4.16). A non-significant effect was observed on TAPSE to PASP ratio and right ventricular global longitudinal strain. Conclusions: Our meta-analysis demonstrates that CRT is associated with a significant improvement in echocardiographic parameters of RV function. Further investigation is necessary to elucidate how these changes, both independently and in conjunction with LV improvement, impact patients’ long-term prognosis, and to identify the specific patient populations expected to derive the greatest benefit.


Introduction
Current guidelines strongly recommend cardiac resynchronization therapy (CRT) due to its demonstrated effect in reducing mortality and hospitalizations among specific heart failure (HF) patient cohorts [1].While the primary goal of CRT is to improve left ventricular function and reduce heart failure symptoms, the impact of CRT on right ventricular (RV) function is also an important consideration.Early studies proposed RV function as an important parameter that foresees the overall and event-free survival of severe HF patients [2,3].However, there is conflicting evidence regarding the role of CRT in RV function, with some studies suggesting that CRT does not have a clinically significant impact on RV function and dimensions [4][5][6].Other studies have reported that CRT contributes to RV function improvement and LV and RV reverse remodeling in patients with systolic dyssynchrony within the left ventricle at follow-up [7][8][9][10][11][12].Sharma established a notable improvement in RV size and function in HF patients which was dependent on age, QRS duration, and baseline left ventricular ejection fraction (LVEF) [13].In the present meta-analysis, we sought to evaluate the effect of CRT on RV function using additional echocardiographic parameters.

Methods
This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines (PRISMA Statement) [14].The protocol of this meta-analysis was registered a priori in the Open Science Framework repository (https://osf.io/wb9pj/)and was adhered to without deviations.

Search Strategy
Two independent investigators conducted a comprehensive search in the MEDLINE and Embase databases, as well as the Cochrane Library, from inception to 18 March 2024.No restrictions were imposed (Supplementary Tables S1-S3).The following terms were utilized to gather all pertinent studies: "RV fractional area change", "RVFAC", "tricuspid annular plane systolic excursion", "TAPSE", "right ventricular function", "cardiac resynchronization therapy", and "biventricular pacemaker".Additionally, the reference lists of identified studies were manually searched.

Eligibility Criteria
We included randomized clinical trials (RCTs) and observational studies that reported RV echocardiographic parameters before and after CRT.Participants were adults (over 18) who met the European Guidelines for CRT at the time of each study.Although all RV parameters were considered, only data on RVFAC (right ventricular fractional area change), RVGLS (right ventricular global longitudinal strain), TAPSE (tricuspid annular plane systolic excursion), S' (myocardial systolic excursion velocity), PASP (systolic pulmonary artery pressure), and the TAPSE/PASP ratio were sufficient for meta-analysis.We excluded studies written in a language other than English and those involving congenital heart disease cases.

Data Extraction
Subsequent information was retrieved from each study: publication details, patient characteristics (including overall number of patients, mean age, sex percentages, cardiomyopathy category, left ventricular ejection fraction (LVEF), the presence of atrial fibrillation (AF), and the presence of left bundle branch block (LBBB)).Additionally, the type of right RV indices provided in each study, along with the raw data of these indices before and after CRT, were documented (Tables 1 and 2).For any missing outcome data, the authors of the primary studies were contacted.Data extraction was performed independently by two investigators.

Quality Assessment
The quality assessment of the included studies was conducted using the Newcastle-Ottawa Quality Assessment Scale (NOS) by two independent researchers.The NOS scoring system comprises three sections: participant selection, result comparability, and outcome quality.Each item specified with a number in the Selection and Outcome categories can receive up to one star, while those in the Comparability category can receive up to two stars.The scale ranges from null to nine stars, with studies classified as low quality if the score is less than 5, fair if the score is between 5 and 7, and good if the score is 8 or higher.

Statistical Analysis
Data analysis was conducted with R software v. 4.2 (R Foundation for Statistical Computing, Vienna, Austria).We conducted a quantitative synthesis regarding the difference between RV indices of RVFAC, RVGLS, TAPSE, S', SPAP, and TAPSE/PASP ratio before and after CRT.Continuous outcome variables were pooled as mean differences (MD) with 95% confidence intervals (CI).We employed a random-effects model with inverse-variance weighting for the analyses.To assess publication bias, we utilized funnel plots and conducted Egger's test.Subgroup analysis according to the follow-up time and responder/non-responder status was also conducted.The I 2 index determines the heterogeneity across studies.A P-value of less than 0.05 (two-tailed) was considered statistically significant.Leave-one-out sensitivity analysis sorted by effect size on the association between cardiac resynchronization therapy and change in TAPSE, PASP, TAPSE/PASP, RVFAC, S', and RVGLS was also performed.For the main analyses with an adequate number of studies, meta-regression analysis was performed to investigate sources of heterogeneity and the effect of possible effect modifiers, namely the year of publication, follow-up time (in years), age (in years), male sex, baseline LVEF, baseline LVEDV, baseline QRS, baseline NYHA class II-III, ischemic cardiomyopathy, diabetes, hypertension, and the use of ACEI/ARBs, beta-blockers, and diuretics on the difference in TAPSE before and after CRT implantation.A similar analysis was performed for RVFAC and PASP.Data regarding other RV function parameters was inadequate for a meta-regression analysis.Statistically significant results required a p-value of more than 0.05.

Results
In total, 30 relevant studies [4,5,[7][8][9][10][11] were included in the analysis (Supplementary Figure S1).The list of excluded studies with rationale is presented in Supplementary Table S4.Of the echocardiographic indices before and after CRT, only RVFAC, RVGLS, TAPSE, S', SPAP, and TAPSE/PASP had adequate information for quantitative synthesis.Based on NOS, the quality of twenty-nine studies was deemed as fair and one study was deemed as being of good quality (Supplementary Table S5).

Small Study Effects and Leave-One-Out Sensitivity Analyses
No evidence of small study effects (including publication bias) was observed following the inspection of funnel plots and the Egger's tests (Supplementary Figures S13-S16).The leave-one-out sensitivity analyses did not show any outliers or influential studies (Supplementary Figures S17-S22).

Subgroup Analyses
The results of the subgroup analyses based on the response in CRT are presented in Supplementary Figures S2-S7.Briefly, CRT resulted in a significant improvement in PASP from baseline for both responders and non-responders.However, significant improvements in the remaining echocardiographic parameters were observed only for the responders to CRT.Subgroup analyses based on the timing of the echocardiographic study indicated that the increase in TAPSE and RVFAC was more profound at 12 months compared to 6 months post CRT implantation (Supplementary Figures S8-S12).

Meta-Regression Analyses
Most of the performed meta-regression analyses failed to explain a significant proportion of the heterogeneity, as described by R 2 (Supplementary Tables S6-S8).Studies with longer follow-up periods reported significantly greater improvements in TAPSE and RVFAC (Figure 3).The baseline LV ejection fraction had no significant impact on the post-intervention improvements in the outcomes of interest.Nevertheless, baseline endsystolic and end-diastolic LV volumes were inversely associated with the reduction in PASP following CRT implementation (Supplementary Table S8).

Discussion
Our metanalysis indicates an improvement in TAPSE, S', and RVFAC as well as a reduction in SPAP after CRT implantation, demonstrating an improvement in RV function.With regards to RVGLS and TAPSE/PASP, we could not find a significant difference after CRT implantation.We confirmed these findings in a subgroup analysis of

Discussion
Our metanalysis indicates an improvement in TAPSE, S', and RVFAC as well as a reduction in SPAP after CRT implantation, demonstrating an improvement in RV function.With regards to RVGLS and TAPSE/PASP, we could not find a significant difference after CRT implantation.We confirmed these findings in a subgroup analysis of studies with a 6-and 12-month follow-up regarding TAPSE increase, studies with a 6-and 12-month follow-up regarding RVFAC increase, studies with a 6-and 12-month follow-up regarding SPAP decrease, and the 6-month follow-up study concerning S' increase.We could not confirm these findings in a subgroup analysis of studies with a 6-and 12-month follow-up concerning RVGLS increase.The increase in TAPSE and RVFAC was greater at 12 months compared to 6 months.This observed trend toward a continuous improvement of RV function according to follow-up time could be further assessed and potentially confirmed in studies with even longer follow-up periods.In the subgroup analysis according to CRT response status, a significant increase in TAPSE, RVFAC, and S' was confirmed only in the responders group.A significant decrease in PASP was confirmed both in responders and non-responders.This finding cannot be explained solely by the existing binary terminology of CRT response and underlines the need for the substitution of this term by the concept of disease modification [41].In this regard, the decrease in PASP could reflect a stabilization of HF or a slowing of LV function deterioration, suggesting partial remission of the disease [41].The increase in TAPSE after CRT implantation was dependent on follow-up time and male sex, while the increase in RVFAC was dependent on follow-up time, baseline LVEF, QRS width, NYHA class II-III, and the use of ACEI/ARB.PASP decrease was dependent on baseline LVESV, LVEDV, and diuretic use.
The existing data regarding the effect of CRT on RV function are somewhat conflicting.The first evaluation of RV remodeling after CRT was conducted by Bleeker et al. [4].Significant RV reverse remodeling did not appear immediately after CRT but was observed at follow-up, with a notable decrease in tricuspid valve short axis, long axis, and annulus dimensions, particularly in patients with the largest RV size at baseline.Donal et al. [5] examined the early effects of CRT on RV function using myocardial strain imaging.Although RV dimensions were similar at baseline and the 3-month follow-up, there was an improvement in TAPSE, RV lateral wall basal strain, and mid strain.In a post hoc analysis of the MADIT-CRT trial [6], patients were randomized into two groups: one receiving CRT with a defibrillator (CRT-D) and the other receiving only an implantable cardioverter defibrillator (ICD).The CRT-D group demonstrated significantly greater improvements in RV function and a reduction in tricuspid regurgitation (TR) compared to the ICD-only group at the 1-year follow-up.
In contrast, studies by Scuteri et al. [7] and Boriani et al. [42] did not find any significant changes in RV dimensions and function at 6 and 3 months, respectively, after CRT implantation.Similarly, a substudy of the REVERSE trial by Kjaergaard et al. [43] including patients with NYHA functional class I and II symptoms, found no clinically significant changes in TAPSE and SPAP at 12-month follow-up both in CRT ON and CRT OFF groups, concluding that CRT does not have a clinically significant effect on TAPSE.In addition, an analysis of the CARE-HF trial [44], showed no improvement in RV function (as assessed by changes in TAPSE and RVFAC) and RV structure (as assessed by right ventricular end-systolic area), both in the presence and absence of ischemic heart disease.
In a prospective study of 905 patients by Leong et al. [40], TAPSE increased, and right ventricular systolic pressure (RVSP) decreased at a 6-month follow-up.The improvement of TAPSE was independent of LVEF change and mitral regurgitation (MR) reduction.These findings suggest that the improvement in RV function indices was associated with a decrease in LV filling pressures, which can indirectly affect RV function.On the contrary, LV systolic function amelioration and MR reduction were not associated with RV function improvement.These findings suggest that CRT affects RV function both directly and indirectly through the enhancement of LV diastolic function.
In a single-center study conducted by Abdelhamid et al. [22], 94 patients were divided into volumetric responders (left ventricular end-systolic volume (LVESV) increase by 15% or more) and non-responders with a follow-up period of 6 months.At the end of the follow-up period, only the responders showed a significant reduction in RV transverse and longitudinal dimensions.Additionally, RV systolic function as measured by RVFAC, TAPSE, S', and RVGLS showed significant improvement only in the responders' group.
TAPSE is an easily obtainable parameter for evaluating RV longitudinal shortening and correlates well with right ventricular ejection fraction (RVEF) [45].However, it is important to note that TAPSE has limitations, including its exclusive focus on assessing the longitudinal shortening of the RV free wall without accounting for the contribution of the remaining walls [46].Additionally, TAPSE is an angle-dependent parameter that is sensitive to changes in preload and afterload.These limitations should be considered when interpreting TAPSE measurements in clinical practice.RVFAC correlates well with RVEF calculated using MRI but relies on clear endocardial border delineation, which can be challenging in an RV with excessive trabeculation and is also influenced by load status [46].Therefore, while RVFAC can provide valuable insights into right ventricular function, its interpretation should take into consideration the above-mentioned potential limitations.
Due to the complexity of the RV, multiple echocardiographic parameters were used in this study to estimate the effect of CRT on RV function.Systolic excursion velocity, also known as S', shows good correlations to radionuclide angiography and cardiac magnetic resonance (CMR)-derived RVEF [47].Right ventricular-arterial coupling (assessed using TAPSE/PASP ratio) has been identified as an independent predictor of mortality in heart failure patients with both reduced and preserved ejection fraction [48].Furthermore, this ratio demonstrates a strong correlation with exercise capacity, with improvements in RVarterial coupling (indicated by an increased TAPSE/PASP ratio) observed only as a result of chronic CRT through reverse remodeling during exercise [36].
Lastly, given the emergence of novel cardiac pacing techniques, including conduction system pacing, future research is needed to thoroughly elucidate their effects on right ventricular function indices, independent of improvements in left ventricular function.

Limitations
This study has certain limitations, primarily attributed to the study design of the published evidence on RV function.First, most of the included studies are observational.There is considerable variability concerning the assessment of particular RV function indices, such as inter-vendor variability in RVGLS analysis.Additionally, some studies had a relatively small number of participants, limiting investigations in specific patient subgroups, and had relatively short follow-up periods.Consequently, future studies with extended follow-up periods are needed to enable a more precise evaluation of the long-term effects of CRT on RV function.

Conclusions
This meta-analysis shows that CRT implantation improves several echocardiographic parameters of RV function.For some echocardiographic indices, this benefit was linearly associated with the duration of follow-up, suggesting a continuous long-term benefit of CRT on RV function.Of note, even non-responders received a benefit in PASP.Collectively, our data suggest that while the primary goal of CRT is to improve left ventricular function in heart failure patients, there is evidence to suggest that CRT can also have a positive impact on RV function.Ongoing research in this area should aim to identify the patient populations most likely to benefit from CRT and to optimize device implantation and pacing strategies to maximize benefits to RV function.

J 15 Figure 3 .
Figure 3. Bubble plots of the meta-regression between TAPSE (A) and RVFAC (B) and follow-up in the months after CRT implementation.

Figure 3 .
Figure 3. Bubble plots of the meta-regression between TAPSE (A) and RVFAC (B) and follow-up in the months after CRT implementation.

Table 1 .
Baseline characteristics of the included studies.

Table 2 .
Baseline characteristics of the included participants.